小分子 BMP 抑制剂在生理和疾病中的应用。
Applications of small molecule BMP inhibitors in physiology and disease.
机构信息
Division of Cardiovascular Medicine and Center for Inherited Heart Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
出版信息
Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):409-18. doi: 10.1016/j.cytogfr.2009.10.021. Epub 2009 Nov 14.
Abstract
Bone morphogenetic proteins (BMPs) provide critical signals for determining cell fate, specifying gastrulation, embryonic patterning, organogenesis, and the remodeling of diverse tissues. Recent work has suggested that in addition to coordinating pivotal events in development, BMPs may also regulate certain homeostatic physiological processes independently of effects on cell growth or differentiation. We recently described the identification of dorsomorphin, a small molecule inhibitor of BMP type I receptors which inhibits BMP signaling in preference to TGF-beta, Activin, and other ligands of the TGF-beta family. We describe a number of strategies using dorsomorphin and its derivatives as probes to assess the physiologic roles of BMP signaling. We also discuss several potential applications for small molecule BMP inhibitors, including stem cell manipulation, and the therapeutic modification of bone remodeling, heterotopic ossification, and iron homeostasis.
摘要
骨形态发生蛋白（BMPs）为细胞命运的决定、原肠胚形成、胚胎模式形成、器官发生以及各种组织的重塑提供了关键信号。最近的研究表明，BMPs 除了协调发育过程中的关键事件外，还可能独立于对细胞生长或分化的影响来调节某些稳态生理过程。我们最近描述了一种小分子抑制剂 dorsomorphin 的鉴定，该抑制剂是 BMP Ⅰ型受体的抑制剂，优先抑制 BMP 信号，而不是 TGF-β、激活素和 TGF-β 家族的其他配体。我们描述了使用 dorsomorphin 及其衍生物作为探针来评估 BMP 信号生理作用的多种策略。我们还讨论了小分子 BMP 抑制剂的几种潜在应用，包括干细胞操作以及对骨重塑、异位骨化和铁稳态的治疗性修饰。
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本文引用的文献
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Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APP(swe)/PS1(DeltaE9) transgenic mouse model of Alzheimer's disease.在阿尔茨海默病的APP（swe）/PS1（DeltaE9）转基因小鼠模型中，头蛋白（Noggin）和骨形态发生蛋白4（BMP4）共同调节成年海马神经发生。
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Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis.骨形态发生蛋白异二聚体组装异源三聚体I型受体复合物以形成背腹轴模式。
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Lack of the bone morphogenetic protein BMP6 induces massive iron overload.骨形态发生蛋白BMP6的缺失会导致大量铁过载。
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Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1.典型和非典型进行性骨化性纤维发育不良（FOP）表型是由骨形态发生蛋白（BMP）I型受体ACVR1中的突变引起的。
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